The bacterial pathogens N. meningitidis and N. gonorrhoeae adhere to and invade human cells, and are capable of inducing a strong inflammatory response. This project focuses on the role of sulfated polysaccharides in bacterial pathogenesis. We demonstrated that sulfated polysaccharides (i.e., glycosaminoglycans) play a key role in gonococcal Opa protein- and meningococcal Opc adhesin-mediated adherence to and invasion of certain types of epithelial cells by acting as host cell receptors for distinct bacterial surface adhesins (OpaA, Opc). In certain cell types, bacterial invasion required the formation of a ternary Opa-polysaccharide-vitronectin complex which in turn bound to epithelial cell receptors resulting in uptake of the pathogen by the epithelial cells. Using a biochemical approach in combination with infection experiments, we were able to demonstrate that serum contains soluble sulfated polysaccharides, and that these compounds have infection inhibitory activity in vitro. These findings are particularly relevant in the light of the increasing number of bacterial pathogens, parasites, and viruses that are capable of interacting with epithelial cells through glycosaminoglycan moieties that are present at the mammalian cell surface. Considering the potential impact on a broad field of infectious diseases and the possible use of sulfated polysaccharides as infection-inhibitory compounds, future work will be directed towards defining the molecular details of the adhesin-polysaccharide-vitronectin complex formation and the function of the soluble sulfated polysaccharides present in serum. The latter is important to evaluate their therapeutic potential as infection-inhibitory compounds.